Tamayo, E. (Esther)
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- Biodegradation and heart retention of polymeric microparticles in a rat model of myocardial ischemia(Elsevier, 2013) Blanco-Prieto, M.J. (María José); Díaz-Herráez, P. (Paula); Tamayo, E. (Esther); Garbayo, E; Prosper-Cardoso, F. (Felipe); Formiga, F.R. (Fabio R.); Simon-Yarza, T. (Teresa); Abizanda-Sarasa, G. (Gloria)Poly-lactide-co-glycolide (PLGA) microparticles emerged as one of the most promising strategies to achieve site-specific drug delivery. Although these microparticles have been demonstrated to be effective in several wound healing models, their potential in cardiac regeneration has not yet been fully assessed. The present work sought to explore PLGA microparticles as cardiac drug delivery systems. PLGA microparticles were prepared by Total Recirculation One-Machine System (TROMS) after the formation of a multiple emulsion. Microparticles of different size were prepared and characterized to select the most suitable size for intramyocardial administration. Next, the potential of PLGA microparticles for administration in the heart was assessed in a MI rat model. Particle biodegradation over time and myocardial tissue reaction were studied by routine staining and confocal microscopy. Results showed that microparticles with a diameter of 5 μm were the most compatible with intramyocardial administration in terms of injectability through a 29-gauge needle and tissue response. Particles were present in the heart tissue for up to three months post-implantation and no particle migration towards other solid organs was observed, demonstrating good myocardial retention. CD68 immunolabeling revealed 31%, 47% and below 4% microparticle uptake by macrophages one week, one month and three months after injection, respectively (P<0.001). Taken together, these findings support the feasibility of the developed PLGA microparticles as vehicles for delivering growth factors in the infarcted myocardium.
- Controlled delivery of fibroblast growth factor-1 and neuregulin-1 from biodegradable microparticles promotes cardiac repair in a rat myocardial infarction model through activation of endogenous regeneration(Elsevier, 2014) Blanco-Prieto, M.J. (María José); Díaz-Herráez, P. (Paula); Gavira, J.J. (Juan José); Tamayo, E. (Esther); Albiasu, E. (Edurne); Garbayo, E; Prosper-Cardoso, F. (Felipe); Formiga, F.R. (Fabio R.); Pelacho, B. (Beatriz); Simon-Yarza, T. (Teresa); Abizanda-Sarasa, G. (Gloria); Imbuluzqueta, I. (Izaskun)Acidic fibroblast growth factor (FGF1) and neuregulin-1 (NRG1) are growth factors involved in cardiac development and regeneration. Microparticles (MPs) mediate cytokine sustained release, and can be utilized to overcome issues related to the limited therapeutic protein stability during systemic administration. We sought to examine whether the administration of microparticles (MPs) containing FGF1 and NRG1 could promote cardiac regeneration in a myocardial infarction (MI) rat model. We investigated the possible underlying mechanisms contributing to the beneficial effects of this therapy, especially those linked to endogenous regeneration. FGF1- and NRG1-loaded MPs were prepared using a multiple emulsion solvent evaporation technique. Seventy-three female Sprague-Dawley rats underwent permanent left anterior descending coronary artery occlusion, and MPs were intramyocardially injected in the peri-infarcted zone four days later. Cardiac function, heart tissue remodeling, revascularization, apoptosis, cardiomyocyte proliferation, and stem cell homing were evaluated one week and three months after treatment. MPs were shown to efficiently encapsulate FGF1 and NRG1, releasing the bioactive proteins in a sustained manner. Three months after treatment, a statistically significant improvement in cardiac function was detected in rats treated with growth factor-loaded MPs (FGF1, NRG1, or FGF1/NRG1). The therapy led to inhibition of cardiac remodeling with smaller infarct size, a lower fibrosis degree and induction of tissue revascularization. Cardiomyocyte proliferation and progenitor cell recruitment was detected. Our data support the therapeutic benefit of NRG1 and FGF1 when combined with protein delivery systems for cardiac regeneration. This approach could be scaled up for use in pre-clinical and clinical studies.
- Profilaxis antibiótica en cirugía(Alpe, 1992) Rodriguez-Torres, A. (A.); Álvarez-Cienfuegos, J. (Javier); Tamayo, E. (Esther); Benito, C. (C.); Eiros, J.M. (J. M.)Existe una abundantísima documentación en la literatura acerca de la eficacia de los antibióticos utilizados profilácticamente en cirugía (1-10). Probablemente lo más útil para el trabajo diario de un hospital sea la adopción de pautas concretas que permitan ser evaluadas periódicamente a través de la colaboración, entre otros, de anestesistas, cirujanos y microbiólogos (11,12). En esta línea hemos revisado, de una manera intencionadamente esquemática, diversas facetas relativas a la profilaxis antibiótica en cirugía. Para ello comentaremos algunos aspectos generales de profilaxis de la infección postquirúrgica, unas breves normas para la utilización profiláctica de antibióticos y resumiremos determinadas indicaciones en función del tipo de intervención.
- Angiogenic therapy for cardiac repair based on protein delivery systems(Springer, 2012) Blanco-Prieto, M.J. (María José); Tamayo, E. (Esther); Prosper-Cardoso, F. (Felipe); Formiga, F.R. (Fabio R.); Pelacho, B. (Beatriz); Simon-Yarza, T. (Teresa)Cardiovascular diseases remain the first cause of morbidity and mortality in the developed countries and are a major problem not only in the western nations but also in developing countries. Current standard approaches for treating patients with ischemic heart disease include angioplasty or bypass surgery. However, a large number of patients cannot be treated using these procedures. Novel curative approaches under investigation include gene, cell, and protein therapy. This review focuses on potential growth factors for cardiac repair. The role of these growth factors in the angiogenic process and the therapeutic implications are reviewed. Issues including aspects of growth factor delivery are presented in relation to protein stability, dosage, routes, and safety matters. Finally, different approaches for controlled growth factor delivery are discussed as novel protein delivery platforms for cardiac regeneration.
- Vascular endothelial growth factor-delivery systems for cardiac repair: An overview(Ivyspring International Publisher, 2012) Blanco-Prieto, M.J. (María José); Tamayo, E. (Esther); Prosper-Cardoso, F. (Felipe); Formiga, F.R. (Fabio R.); Pelacho, B. (Beatriz); Simon-Yarza, T. (Teresa)Since the discovery of the Vascular Endothelial Growth Factor (VEGF) and its leading role in the angiogenic process, this has been seen as a promising molecule for promoting neovascularization in the infarcted heart. However, even though several clinical trials were initiated, no therapeutic effects were observed, due in part to the short half life of this factor when administered directly to the tissue. In this context, drug delivery systems appear to offer a promising strategy to overcome limitations in clinical trials of VEGF. The aim of this paper is to review the principal drug delivery systems that have been developed to administer VEGF in cardiovascular disease. Studies published in the last 5 years are reviewed and the main features of these systems are explained. The tissue engineering concept is introduced as a therapeutic alternative that holds promise for the near future.
- PEGylated-PLGA microparticles containing VEGF for long term drug delivery(Elsevier, 2013) Blanco-Prieto, M.J. (María José); Tamayo, E. (Esther); Prosper-Cardoso, F. (Felipe); Formiga, F.R. (Fabio R.); Pelacho, B. (Beatriz); Simon-Yarza, T. (Teresa)The potential of poly(lactic-co-glycolic) acid (PLGA) microparticles as carriers for vascular endothelial growth factor (VEGF) has been demonstrated in a previous study by our group, where we found improved angiogenesis and heart remodeling in a rat myocardial infarction model (Formiga et al., 2010). However, the observed accumulation of macrophages around the injection site suggested that the efficacy of treatment could be reduced due to particle phagocytosis. The aim of the present study was to decrease particle phagocytosis and consequently improve protein delivery using stealth technology. PEGylated microparticles were prepared by the double emulsion solvent evaporation method using TROMS (Total Recirculation One Machine System). Before the uptake studies in monocyte-macrophage cells lines (J774 and Raw 264.7), the characterization of the microparticles developed was carried out in terms of particle size, encapsulation efficiency, protein stability, residual poly(vinyl alcohol) (PVA) and in vitro release. Microparticles of suitable size for intramyocardial injection (5 mu m) were obtained by TROMS by varying the composition of the formulation and TROMS conditions with high encapsulation efficiency (70-90%) and minimal residual PVA content (0.5%). Importantly, the bioactivity of the protein was fully preserved. Moreover, PEGylated microparticles released in phosphate buffer 50% of the entrapped protein within 4 h, reaching a plateau within the first day of the in vitro study. Finally, the use of PLGA microparticles coated with PEG resulted in significantly decreased uptake of the carriers by macrophages, compared with non PEGylated microparticles, as shown by flow cytometry and fluorescence microscopy. On the basis of these results, we concluded that PEGylated microparticles loaded with VEGF could be used for delivering growth factors in the myocardium.
- A simple and efficient method for the production of human glycosylated glial cell line-derived neurotrophic factor using a Semliki Forest virus expression system(Elsevier, 2013) Blanco-Prieto, M.J. (María José); Smerdou, C. (Cristian); Aymerich-Soler, M.S. (María Soledad); Tamayo, E. (Esther); Ansorena-Artieda, E. (Eduardo); Casales, E. (Erkuden); Garbayo, E; Aranda, A. (Alejandro)Human glial cell line-derived neurotrophic factor (hGDNF) is a very promising protein for the treatment of Parkinson's disease and other neurodegenerative disorders. The present work describes a quick and simple method to obtain a high amount of purified hGDNF using a mammalian cell-derived system. The method is based on the high expression level provided by a Semliki Forest virus vector and its ability to induce a strong shut-off of host-cell protein synthesis in mammalian cells. As a result, hGDNF is the only protein present in the supernatant and can be efficiently purified by a single chromatographic step. Using this system it was possible to eliminate other secreted proteins from the culture medium, like insulin-like growth factor-5, which are hard to remove using other hGDNF production methods. Purified hGDNF presents a complex glycosylation pattern typical of mammalian expression systems and is biologically active. This protocol could be extended to other secreted proteins and could be easily scaled up for industrial purposes.
- Functional benefits of PLGA particulates carrying VEGF and CoQ10 in an animal of myocardial ischemia(Elsevier, 2013) Blanco-Prieto, M.J. (María José); Ortiz-de-Solorzano, C. (Carlos); Grama, C.R. (Charitra N.); Tamayo, E. (Esther); Ravi-Kumar, M.N.V. (M.N.V.); Benavides, C. (Carolina); Prosper-Cardoso, F. (Felipe); Formiga, F.R. (Fabio R.); Simon-Yarza, T. (Teresa); Lana, H. (Hugo)Myocardial ischemia (MI) remains one of the leading causes of death worldwide. Angiogenic therapy with the vascular endothelial growth factor (VEGF) is a promising strategy to overcome hypoxia and its consequences. However, from the clinical data it is clear that fulfillment of the potential of VEGF warrants a better delivery strategy. On the other hand, the compelling evidences of the role of oxidative stress in diseases like MI encourage the use of antioxidant agents. Coenzyme Q10 (CoQ10) due to its role in the electron transport chain in the mitochondria seems to be a good candidate to manage MI but is associated with poor biopharmaceutical properties seeking better delivery approaches. The female Sprague Dawley rats were induced MI and were followed up with VEGF microparticles intramyocardially and CoQ10 nanoparticles orally or their combination with appropriate controls. Cardiac function was assessed by measuring ejection fraction before and after three months of therapy. Results demonstrate significant improvement in the ejection fraction after three months with both treatment forms individually; however the combination therapy failed to offer any synergism. In conclusion, VEGF microparticles and CoQ10 nanoparticles can be considered as promising strategies for managing MI.
- Sustained release of VEGF through PLGA microparticles improves vasculogenesis and tissue remodeling in an acute myocardial ischemia–reperfusion model(Elsevier, 2010) Blanco-Prieto, M.J. (María José); Gavira, J.J. (Juan José); Ortiz-de-Solorzano, C. (Carlos); Tamayo, E. (Esther); Mazo, M. (Manuel); Jauquicoa, C. (Carlos); Garbayo, E; Prosper-Cardoso, F. (Felipe); Formiga, F.R. (Fabio R.); Pelacho, B. (Beatriz); Simon-Yarza, T. (Teresa); Abizanda-Sarasa, G. (Gloria)The use of pro-angiogenic growth factors in ischemia models has been associated with limited success in the clinical setting, in part owing to the short lived effect of the injected cytokine. The use of a microparticle system could allow localized and sustained cytokine release and consequently a prolonged biological effect with induction of tissue revascularization. To assess the potential of VEGF165 administered as continuous release in ischemic disease, we compared the effect of delivery of poly(lactic–co-glycolic acid) (PLGA) microparticles (MP) loaded with VEGF165 with free-VEGF or control empty microparticles in a rat model of ischemia–reperfusion. VEGF165 loaded microparticles could be detected in the myocardium of the infarcted animals for more than a month after transplant and provided sustained delivery of active protein in vitro and in vivo. One month after treatment, an increase in angiogenesis (small caliber caveolin-1 positive vessels) and arteriogenesis (α-SMA-positive vessels) was observed in animals treated with VEGF microparticles (pb0.05), but not in the empty microparticles or free-VEGF groups. Correlating with this data, a positive remodeling of the heart was also detected in the VEGF-microparticle group with a significantly greater LV wall thickness (pb0.01). In conclusion, PLGA microparticle is a feasible and promising cytokine delivery system for treatment of myocardial ischemia. This strategy could be scaled up and explored in pre-clinical and clinical studies.